Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks

Juan Bayo, Tram Anh Tran, Lei Wang, Samuel Peña-Llopis, Amit K. Das, Elisabeth D. Martinez

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

We have uncovered a role for Jumonji inhibitors in overcoming radioresistance through KDM5B inhibition. Pharmacological blockade of Jumonji demethylases with JIB-04 leads to specific accumulation of H3K4me3 at sites marked by γH2AX and impaired recruitment of DNA repair factors, preventing resolution of damage and resulting in robust sensitization to radiation therapy. In DNA-repair-proficient cancer cells, knockdown of the H3K4me3 demethylase KDM5B, but not other Jumonji enzymes, mimics pharmacological inhibition, and KDM5B overexpression rescues this phenotype and increases radioresistance. The H3K4me3 demethylase inhibitor PBIT also sensitizes cancer cells to radiation, while an H3K27me3 demethylase inhibitor does not. In vivo co-administration of radiation with JIB-04 significantly prolongs the survival of mice with tumors even long after cessation of treatment. In human patients, lung squamous cell carcinomas highly expressing KDM5B respond poorly to radiation. Thus, we propose the use of Jumonji KDM inhibitors as potent radiosensitizers. Radioresistance is an obstacle to lung cancer cures. Bayo et al. reveal that JARID1B removes H3K4me3 marks at sites of DNA damage. Genetic or pharmacological inhibition of JARID1B robustly radiosensitizes cancers in vitro and in vivo through defects in DNA repair, providing a therapeutic option for radioresistant tumors.

Original languageEnglish (US)
Pages (from-to)1040-1050.e5
JournalCell Reports
Volume25
Issue number4
DOIs
StatePublished - Oct 23 2018

Fingerprint

Methylation
Repair
DNA Repair
DNA
Radiation
Tumors
Pharmacology
Neoplasms
Cells
Radiotherapy
Withholding Treatment
DNA Damage
Squamous Cell Carcinoma
Lung Neoplasms
Defects
Phenotype
Enzymes
Lung
JIB-04

Keywords

  • DNA repair
  • H3K4me3
  • JARID
  • JIB-04
  • Jumonji KDM
  • KDM5B
  • lung cancer
  • radiation therapy
  • radioresistance
  • radiosensitization

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks. / Bayo, Juan; Tran, Tram Anh; Wang, Lei; Peña-Llopis, Samuel; Das, Amit K.; Martinez, Elisabeth D.

In: Cell Reports, Vol. 25, No. 4, 23.10.2018, p. 1040-1050.e5.

Research output: Contribution to journalArticle

Bayo, Juan ; Tran, Tram Anh ; Wang, Lei ; Peña-Llopis, Samuel ; Das, Amit K. ; Martinez, Elisabeth D. / Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks. In: Cell Reports. 2018 ; Vol. 25, No. 4. pp. 1040-1050.e5.
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AB - We have uncovered a role for Jumonji inhibitors in overcoming radioresistance through KDM5B inhibition. Pharmacological blockade of Jumonji demethylases with JIB-04 leads to specific accumulation of H3K4me3 at sites marked by γH2AX and impaired recruitment of DNA repair factors, preventing resolution of damage and resulting in robust sensitization to radiation therapy. In DNA-repair-proficient cancer cells, knockdown of the H3K4me3 demethylase KDM5B, but not other Jumonji enzymes, mimics pharmacological inhibition, and KDM5B overexpression rescues this phenotype and increases radioresistance. The H3K4me3 demethylase inhibitor PBIT also sensitizes cancer cells to radiation, while an H3K27me3 demethylase inhibitor does not. In vivo co-administration of radiation with JIB-04 significantly prolongs the survival of mice with tumors even long after cessation of treatment. In human patients, lung squamous cell carcinomas highly expressing KDM5B respond poorly to radiation. Thus, we propose the use of Jumonji KDM inhibitors as potent radiosensitizers. Radioresistance is an obstacle to lung cancer cures. Bayo et al. reveal that JARID1B removes H3K4me3 marks at sites of DNA damage. Genetic or pharmacological inhibition of JARID1B robustly radiosensitizes cancers in vitro and in vivo through defects in DNA repair, providing a therapeutic option for radioresistant tumors.

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